Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, 2900, Hellerup, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetologia. 2018 Feb;61(2):413-423. doi: 10.1007/s00125-017-4447-4. Epub 2017 Sep 25.
AIMS/HYPOTHESIS: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH in in vivo and in in vitro receptor studies.
In transiently transfected COS-7 cells, GIP(3-30)NH was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20-30 years, HbA less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH (800 pmol kg min), GIP (1.5 pmol kg min), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out.
GIP(3-30)NH neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p < 0.0001) during co-infusion with GIP(3-30)NH, and the need for glucose was reduced to placebo levels. There were no effects of GIP(3-30)NH alone or of GIP with or without GIP(3-30)NH on plasma glucagon, GLP-1, somatostatin, triacylglycerols, cholesterol, glycerol or NEFA. GIP(3-30)NH administration was well tolerated and without side effects.
CONCLUSIONS/INTERPRETATION: We conclude that GIP(3-30)NH is an efficacious and specific GIP receptor antagonist in humans suitable for studies of GIP physiology and pathophysiology.
ClinicalTrials.gov registration no. NCT02747472.
The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.
目的/假设：葡萄糖依赖性胰岛素促分泌多肽（GIP）是一种肠内分泌 K 细胞餐后分泌的肠促胰岛素激素，但尽管具有治疗上的有趣作用，人类的 GIP 生理学仍不完全了解。在这一领域的进展可以通过适当的 GIP 受体拮抗剂来促进。我们首次在人体中研究了天然存在的 GIP(3-30)NH 在体内和体外受体研究中的拮抗特性。
在瞬时转染的 COS-7 细胞中，使用同源受体结合和受体激活（cAMP 积累）研究评估 GIP(3-30)NH 在胰高血糖素样肽 1 (GLP-1)、胰高血糖素样肽-2 (GLP-2)、胰高血糖素、分泌素和生长激素释放激素 (GHRH) 受体上的作用。10 名健康男性（入选标准：年龄 20-30 岁，HbA<6.5%[48mmol/mol]和空腹血糖[FPG]<7mmol/l）被纳入临床研究。数据作为来自肘静脉插管的血浆和血清样本收集。作为主要结果，通过在高血糖钳夹实验中以随机、四期、交叉设计输注 GIP(3-30)NH（800pmolkgmin）、GIP（1.5pmolkgmin）、这些的组合或安慰剂，评估胰岛素分泌和葡萄糖需求。输注的内容对研究参与者和实验人员都是盲目的。没有研究参与者退出。
GIP(3-30)NH 既不结合，也不刺激或拮抗体外一系列相关受体。GIP(3-30)NH 在人体内的消除血浆半衰期为 7.6±1.4 分钟。与其他日子相比，在 GIP 输注期间需要更多的葡萄糖来维持钳夹。GIP 诱导的胰岛素分泌在与 GIP(3-30)NH 共同输注时减少了 82%（p<0.0001），并且对葡萄糖的需求降低到安慰剂水平。GIP(3-30)NH 单独或与 GIP 联合或不联合 GIP(3-30)NH 对血浆胰高血糖素、GLP-1、生长抑素、三酰甘油、胆固醇、甘油或非酯化脂肪酸均无影响。GIP(3-30)NH 给药耐受良好，无副作用。
结论/解释：我们得出结论，GIP(3-30)NH 是一种在人类中有效的、特异性的 GIP 受体拮抗剂，适用于 GIP 生理学和病理生理学的研究。
ClinicalTrials.gov 注册号 NCT02747472。
该研究由 Gangsted 基金会、欧洲糖尿病研究基金会和 Aase og Ejnar Danielsens 基金会资助。
